ANGI-12EFFICACY OF THE PENTRA®BODY DLX1008, A MONOVALENT ANTIBODY FRAGMENT WITH LOW PICOMOLAR AFFINITY TO VEGF-A, IN HUMAN GLIOMA MODELS IN VITRO AND IN VIVO

N E U R O - O N C O L O G Y

Abstracts

ANGI-12. EFFICACY OF THE PENTRAw

BODY DLX1008, A MONOVALENT ANTIBODY FRAGMENT WITH LOW PICOMOLAR AFFINITY TO VEGF-A, IN HUMAN GLIOMA MODELS IN VITRO AND IN VIVO

Emese Szabo1_{, Douglas Phillips}2_{, Japar Shamshiev}2_{, Miriam Steinwand}2_,

Nicole Dreier2_{, AnnaBianca Howald}2_{, Marco Landi}2_{, Andrea Marti}2_,

Camilla Winnewisser2_{, Julia Molitor}2_{, Titus Kretzschmar}2_{, and}

Michael Weller1_;1_{Laboratory of Molecular Neuro-Oncology, Department of}

Neurology, University Hospital and University of Zurich, Zurich, Switzerland;2_{Delenex Therapeutics AG, Schlieren, Switzerland}

Angiogenesis mediated by vascular endothelial growth factor (VEGF) is a hallmark of glioblastoma. Moreover, VEGF may exert tumor-intrinsic sur-vival properties mediated both by VEGF receptors 1 and 2. Although various VEGF inhibitors have shown limited clinical activity in glioblastoma,

notably determined by responses on neuroimaging and prolongation of progression-free survival (PFS), no VEGF antagonist has so far been demon-strated to unequivocally improve overall survival in any clinical setting in glio-blastoma. Based on response rates and improved PFS, although not overall survival (OS), the 149 kDa anti-VEGF-A IgG antibody bevacizumab (Avastinw_{) is approved in the US and Japan for recurrent glioblastoma and}

in Japan for newly diagnosed glioblastoma. However, it is not approved in the EU. Here we characterize DLX1008, a 26 kDa anti-VEGF-A single chain antibody fragment which binds with 22 pM and 27 pM affinity to mouse and human VEGF-A, respectively. In vitro, in a tube formation assay with human cerebral microvascular endothelial cells (HCMEC), it was dem-onstrated that DLX1008 is at least as active as Avastinw_{. In addition,}

DLX1008 showed superiority to Avastinw_{in the inhibition of VEGF-A}

binding to VEGF-R1 in ELISA by a factor of around 10. In vivo, DLX1008 sig-nificantly improved survival in a mouse orthotopic U87 xenograft model com-pared to vehicle control (p ¼ 0.00026) and significantly inhibited tumor growth in a mouse subcutaneous U87 xenograft model compared to vehicle control (p ¼ 0.0021). In summary, these data warrant further clinical develop-ment of DLX1008 in a biomarker-driven approach to glioblastoma. DLX1008 may provide improved clinical benefit in glioblastoma, especially in overall survival, due to higher affinity and smaller size leading to improved tumor penetration.

Neuro-Oncology 17:v41 – v44, 2015.

doi:10.1093/neuonc/nov207.12